DESCRIPTION: Cystitis is an extremely common clinical disorder. Although a majority of clinical cases of cystitis are due to infectious causes, cystitis in the apparent absence of infectious agents is commonly diagnosed. The pathogenesis of cystitis in many of these patients remains unknown. Interstitial cystitis (IC) is a diagnosis which has been applied to a specific subset of these patients suffering from chronic cystitis in the absence of a known etiology. Previous reports indicate that IC is accompanied by increased nerve density within the bladder wall. Neurogenic inflammation due to stimulation of sensory nerves and subsequent discharge of neuropeptides has been described in a variety of tissues, including the bladder, and administration of exogenous SP causes plasma extravasation, extravascular accumulation of leukocytes, and mast cell degranulation in the bladder and other tissues. Although it has been proposed that mast cells play a critical role in some forms of cystitis and some experimental evidence suggests that the inflammatory effects of neuropeptides are largely dependent upon mast cell degranulation, these issues remain unclear. Regardless of the cause of inflammation, experimental and clinical studies suggest that neuropeptides play a critical role in the inflammatory response of the bladder to various irritant stimuli. The specific aims of the proposed research are: 1. To determine whether neuropeptides modulate the severity of cystitis induced by antigen sensitization and exposure or by intravesical instillation of E. coli lipopolysaccharide (LPS); 2. To determine whether the effects of neuropeptides on cystitis are dependent upon the presence of mast cells; 3. To determine the effects of inflammation on the presence of SP, CGRP, and SOM in human bladder tissue. These aims will be pursued by use of passively sensitized human bladder tissue, patient biopsies, and murine models of cystitis. The long-range goal of this research is improved understanding of the pathogenesis, treatment, and prevention of inflammatory bladder disorders. Neuropeptides clearly have the capacity to mediate the onset and persistence of cystitis, but the exact nature of their effects on cystitis is unclear. The proposed research should help clarify this and suggest strategies for disease prevention or improved treatment.